U.S. Pat. No. 5,145,684 discloses particles of a drug substance having a surface modifier adsorbed on the surface thereof and methods for the preparation thereof by wet grinding. These particles have demonstrated significant pharmaceutical utility. Suitable surface modifiers described include various polymers. The preferred surface modifiers disclosed include Pluronic F68 and F108, which are block copolymers of ethylene oxide and propylene oxide, and Tetronic 908, which is a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylene diamine.
U.S. Pat. No. 5,318,767 discloses x-ray contrast compositions comprising particles of an x-ray contrast agent having a surface modifier adsorbed on the surface thereof and methods for the preparation thereof by wet grinding. The above-noted surface modifiers are also disclosed as being useful therein. These x-ray contrast compositions have demonstrated remarkable utility in x-ray medical diagnostic imaging procedures.
P. Sarpotdar et al., U.S. patent application Ser. No. 07/988,564 filed Dec. 10, 1992, discloses therapeutic and diagnostic compositions with Olin-10 G, i.e., p-isononylphenoxypoly(glycidol) having improved autoclave stability.
However, some of the above-described polymeric surfactants have demonstrated less than superior toxicological profiles, for example, in a "smudge cell" assay. In addition, these prior art surfactant coatings, on some occasions, have exhibited less than desirable inhibition of macrophage uptake.
Furthermore, sterilization of therapeutic and diagnostic agents in nanoparticulate form stabilized by a surface modifier is difficult. Filtration using a filter of 0.22 .mu.m mesh size is sufficient to remove most bacteria and viruses, but the nanoparticles, due to their sizes, cannot be sterile filtered without accounting for substantial drug losses.
Moreover, the wet grinding methods described in the patents noted above often entail grinding for days or even weeks which can be undesirable, e.g., from the standpoint of process scale-up.
Consequently, it would be highly desirable to provide surfactant coatings for nanoparticles which reduce the smudge cell effect, inhibit macrophage uptake and facilitate particle size reduction such that milling time can be reduced and/or sterile filtration of the nanoparticles can be accomplished without substantial particle losses.